[The Instructions to Authors state no abstract is required for a Research Letter but the submission sysem demands one, so this text is included.] In order to assess whether measuring HE4 might add to the performance of CA125 in diagnosing ovarian cancer, we measured both markers in 33 individuals with elevated CA125. We found that HE4 elevated above 150 pmol/l was present in all 9 cases of ovarian cancer and in the single case of pancreatic cancer.  HE4 levels below 77pmol/l seen in 16 cases were associated with non-malignant gynaecological conditions and with there being no identified cause for elevated CA125. Two cases with HE4 between 77 and 149 pmol/l had no gynaecological conditions and 2 had no an identifiable cause.  Measuring both markers could lead to improved sensitivity and specificity of the initial diagnostic step.

Accuracy of outcome definitions in Mendelian randomization of maternal healthQian Yang,1,2 Maria Carolina Borges1,2 1 MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK2 Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UKDear Dr Papageorphiou,We recently read the article by Dr Ardissino and colleagues entitled ‘Genetically predicted body mass index and maternal outcomes of pregnancy: A two-sample Mendelian randomization study’ [1], where 11 outcomes were investigated. To conduct Mendelian randomization (MR) analyses, this study extracted associations of selected genetic variants with those outcomes from publicly available GWAS (genome-wide association study) summary data from FinnGen (the sixth release, total N=147,061 women) – a national-wide network of Finish Biobank [2]. We noticed that “postpartum depression” included in Ardissino et al was inconsistent with the commonly used definition of postnatal depression occurring within a year of delivery [3,4]. FinnGen defined this outcome based on the International Classification of Diseases 10th Revision (ICD-10) codes (ICD-10 F32, F33 and F53.0) among women with at least one episode of delivery (ICD-10 O80-O84), without considering the time interval between delivery and diagnosis of depression. Therefore, cases of “postpartum depression” could be ascertained at any time after giving birth and, therefore, could be unrelated to pregnancy. As a consequence, findings for “postpartum depression” in Ardissino et al should be interpreted with caution due to the unspecific outcome definition.The increasing availability of publicly available or accessible data from GWAS consortia (e.g. Early Growth Genetics) and large biobanks (e.g. UK Biobank and FinnGen), combined with the creation of automated pipelines (e.g. MR-Base [5] used by Ardissino et al), has supported an rapid increase in publications using two-sample MR. Though such a combination has great potential to promote open science and advance health research, including in maternal-child health, we cautioned that detailed understanding of procedures used to generate GWAS summary data underlying MR analyses is of major importance to obtain reliable evidence and interpretable findings.

Pre-eclampsia and gestational diabetes mellitus are associated with an increased risk of cardiovascular diseaseDear Dr Papageorghiou,We read with great interest the article published in BJOG by Hildén et al.1, in which the authors aimed to investigate if the pre-eclampsia association with cardiovascular disease (CVD) was independent of gestational diabetes mellitus (GDM). They indicated that pre-eclampsia and GDM were independent risk factors for CVD, and after stratifying by maternal body mass index (BMI), the adjusted association of pre-eclampsia with CVD did not differ notably between BMI groups. They concluded that pre-eclampsia and GDM were independent risk factors for later CVD and having both during pregnancy was a major risk factor for later CVD. Furthermore, they indicated that the association between pre-eclampsia and CVD was not modified by BMI.We support the information provided by Hildén et al.1, and hypertension is a mediator of CVD rather than a component of the diagnostic bundle. It has been shown that pre-eclampsia and GDM can affect blood vessels, but it is not clear aetiology2. Previous studies indicated that women with GDM have an increased risk of developing preeclampsia, which in turn increases the risk of developing advanced CVD3,4. However, in these studies, there were many potential confounding factors due to the lack of adjustment for BMI. The current research just filled in this disadvantage. We thank Hildén et al.1 for their comprehensive contribution.We believe that the biggest advantage of this study is that it is a nationwide study, and the data collected prospectively has high credibility. The main disadvantage is that women with diabetes before pregnancy are excluded, which may have a great impact on the research results, leading to bias. This nested case-control study included 2639 cases and 13310 controls with complete data. So large number of study population will provide valuable guidance for clinicians to improve their understanding of pre-eclampsia and GDM related CVD, despite some limitations of this study. In addition, we are also looking forward to Hildén et al.1 developing effective CVD prevention plans for high-risk women to improve their long-term health. Therefore, we believe the research by Muraca et al.1 will greatly promote further researches on the pre-eclampsia and GDM related CVD.

The role of neoadjuvant chemotherapy in advanced Ovarian Cancer (AOC): Avoiding ‘needless hurt’ or a Trojan horse?

A document by Jan Deprest. Click on the document to view its contents.

Objective: to correlate the clinical history with imaging findings of women with MRKH Design: Retrospective cohort study Setting: A UK IOTA and ESGO-certified tertiary referral centre for disorders of reproductive development Population: All patients with a diagnosis of MRKH and had undergone an MRI pelvis between 1st January 2011 – 31st April 2021 were included Method: MRI images were analysed by specialist gynaecological radiologists. Clinical data was extracted from an electronic patient record system. Statistical analysis was computed in R (version 4.1.2), R base stats package and ggstatsplot (v0.5.0). Outcome measures: clinical history and predefined imaging features Results: 134 patients were included. Median age at MRI was 18 years (10 – 64 years). Half (48.2%) of women presenting had a history of pain, most often abdominal (84.6%) or vaginal (9.2%). Anlage were identified in 91.8% of women (n = 123). 4.5% of women had imaging features of endometriosis (n = 6). Women with a functional anlage were significantly more likely to experience pain (p <0.001). Pain history was not strongly associated with ectopic ovarian position. Common gynaecological pathology such as endometriosis, ovarian cysts and fibroids were also identified. Conclusions: We identify that majority of women with MRKH will have uterine anlage with a connecting fibrous band, and an ectopic ovarian position 44.0% of cases. Abdominal pain was significantly associated with functional anlage on MRI. Further work is required to identify how other gynaecological pathology impacts women with MRKH.

A document by Franca Rusconi. Click on the document to view its contents.

Gestational diabetes mellitus, pre-eclampsia and future cardiovascular disease: need to consider both BMI and gestational weight gain to investigate the linkLionel Carbillon1, 3, Amélie Benbara1, Emmanuel Cosson2, 31Department of Obstetrics and Gynecology, Paris-Seine Saint Denis University Hospitals, Assistance Publique – Hopitaux de Paris, Paris 13 University, France2 Department of Endocrinology, Diabetology, Nutrition, Paris-Seine Saint Denis University Hospitals, Assistance Publique – Hôpitaux de Paris, France3Sorbonne North Paris University

SARS-CoV-2 has had a significant impact on pregnancy outcomes due to the effects of the virus and the altered healthcare environment. Stillbirth has been relatively hidden during the COVID-19 pandemic, but a clear link between SARS-CoV-2 and poor fetal outcome emerged in the Alpha and Delta waves. A small minority of women/birthing people who contracted COVID-19 developed SARS-CoV-2 placentitis. In many reported cases this was linked to intrauterine fetal death, although there are cases of delivery just before imminent fetal demise and we shall discuss how some cases are sub-clinical. What is surprising, is that SARS-CoV-2 placentitis is often not associated with severe maternal COVID-19 infection, and this makes it difficult to predict. The worst outcomes seem to be with diffuse placental disease and occurs within 21 days of COVID-19 diagnosis. Poor outcomes are often pre-dated by reduced fetal movements, but are not associated with ultrasound changes. In some cases, there has also been maternal thrombocytopenia, or coagulation abnormalities, which may provide a clue as to which pregnancies are at risk of fetal demise if a further variant of concern is to emerge. In future, multidisciplinary collaboration and cross-boundary working must be prioritised, to quickly identify such a phenomenon and provide clinicians with clear guidance for reducing fetal death and associated poor outcomes. Whilst we wait to see if COVID-19 brings a future variant of concern, we must focus on appropriate future management of women who have had SARS-CoV-2 placentitis. The histopathology reports with pathologies of chronic histiocytic villositis and/or massive perivillous fibrin deposition fill clinicians with concern about future pregnancy outcomes. However, we must remember, that in the context of a cause (SARS-CoV-2) and no other history of concern, it is not likely that SARS-CoV-placentitis will recur, and thus a measured approach to subsequent pregnancy management is needed.

Exposure to extreme heat in pregnancy increases the risk of stillbirth. Progress in reducing stillbirth rates has stalled, and populations are increasingly exposed to high temperatures and climate events that may further undermine health strategies. This narrative review summaries the current clinical and epidemiological evidence of the impact of maternal heat exposure on stillbirth risk. 19 out of 20 studies found an association between heat and stillbirth risk. Recent studies based in low- middle- income countries and tropical settings add to the existing literature to demonstrate that all populations are at risk. Additionally, both short-term heat exposure and whole-pregnancy heat exposure increase the risk of stillbirth. A definitive threshold of effect has not been identified, as most studies define exposure as > 90 th percentile of the usual temperature for that population. Therefore, the association between heat and stillbirth has been found with exposures from as low as >12.64°C up to >46.4°C. The pathophysiological pathways by which maternal heat exposure may lead to stillbirth, based on human and animal studies, include both placental and embryonic or fetal impacts. Although evidence gaps remain and further research is needed to characterise these mechanistic pathways in more detail, preliminary evidence suggests epigenetic changes, alteration in imprinted genes, congenital abnormalities, reduction in placental blood flow, size and function all play a part. Finally, we explore this topic from a public health perspective; we discuss and evaluate the current public health guidance on minimising the risk of extreme heat in the community. There is limited pregnancy specific guidance within heatwave planning, and no evidence-based interventions have been established to prevent poor pregnancy outcomes. We highlight priority research questions to move forward in the field and specifically note the urgent need for evidence-based interventions that are sustainable.

Objective: To examine whether women with a history of hysteroscopic adhesiolysis (HA)-treated intrauterine adhesions (IUAs) were at higher risk of adverse obstetrical outcomes in subsequent pregnancies. Design: Retrospective cohort study. Setting: A tertiary-care hospital in Shanghai, China. Population: 114,142 pregnant women who were issued an antenatal card and received routine antenatal care in Shanghai First Maternity and Infant Hospital between January 2016 and October 2021. Methods: From the cohort of 114,142 pregnant women, women with history of HA-treated IUAs before this pregnancy (N=780) were compared with 4 women with no history of IUAs (N=3010) matched on propensity score, maternal age and parity, mode of conception, pre-pregnancy BMI and prior history of abortion. Main outcome measures: Pregnancy complications, placental abnormalities, postpartum hemorrhage and adverse birth outcomes. Results : Compared with women with no history of IUAs, women with a history of HA-treated IUAs were at higher risks of preeclampsia (RR=1.69, 95% CI, 1.23, 2.33), placenta accreta spectrum (RR=4.72, 95% CI, 3.9, 5.73) and previa (RR=4.23, 95% CI, 2.85, 6.30), postpartum hemorrhage (RR=2.86, 95% CI, 1.94, 4.23), preterm premature rupture of membranes (RR=3.02, 95% CI, 1.97, 4.64) and iatrogenic preterm birth (RR=2.86, 95% CI, 2.14, 3.81) . Those women were also more likely to receive cervical cerclage (RR=5.63, 95% CI, 3.95, 8.02) during pregnancy and hemostatic therapies after delivery (RR=2.17, 95% CI, 1.75, 2.69). Moreover, we observed that the RRs of those adverse obstetrical outcomes increased with the increasing number of hysteroscopic surgeries. Conclusion: Our findings suggest that pregnant women with a history of HA-treated IUAs, especially those with a history of repeat HAs, are at higher risk of adverse obstetrical outcomes. Key words: hysteroscopic adhesiolysis, obstetrical outcomes, propensity score matching, cohort study

Title Guideline consultation generates inevitable challenges but invaluable communication SignatoryPauline McDonagh Hull, Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Alberta, CanadaLetterDear Sir, As first author of one of the BJOG letters cited in Dr. Murphy’s commentary on the ‘unwelcome consequences of guideline authorship’1 (‘Montgomery is missing from RCOG’s Assisted Vaginal Birth guideline’),2 and director of one of the organisations that submitted comments during the Royal College of Obstetricians and Gynaecologists’ consultation, I would appreciate the opportunity to clarify my involvement and position in the matters described, to avoid potential misinterpretations or assumptions where individuals and organisations have not been named. Dr. Murphy mentions ‘individuals who…believe that forceps should be abolished entirely’, and informs readers this view ‘was reflected in one submission…from a patient advocacy organisation who suggested that planned caesarean section should be recommended to women as a means of avoiding AVB.’ She then notes that our Montgomery letter2 ‘repeated the same point about planned caesarean section they had made during the consultation process.’ For the record, the submission from my voluntary organisation, Caesarean Birth, did not suggest forceps should be abolished, and proposed offering, not recommending, planned caesareans. I disagree with Dr. Murphy’s assertion that our letter was ‘hostile’, and we stand by the concerns expressed therein. However, where I do agree with Dr. Murphy is in relation to the irrefutable challenge ‘of reconciling polarised views’. While our criticism of the RCOG guideline may be perceived as ‘an agenda’ to ‘undermine authors’, it may also be perceived as a sincere effort to influence a hegemonic shift in maternity services in the face of unprecedented maternity litigation resulting from avoidable harm. These views may never be fully reconciled, but I believe we all share the same goal of improving health outcomes. Moreover, the RCOG has responded to criticism of its assisted vaginal birth and caesarean birth recommendations in the past; initially removing them from its website temporarily, and then permanently, five years later.3Last year, the University of Aberdeen was awarded almost 1 million GBP to develop a novel decision aid, to be offered to all women, for planning mode of birth.4 In my view, the option of planned caesarean birth should not be reserved for obstetricians or women who initiate discussions, as this does not constitute equitable care. Language in maternity services is changing too. While Dr. Murphy refers to ‘caesarean section’, both the RCOG and National Institute for Health and Care Excellence (NICE) adopted ‘caesarean birth’ for their respective 2021 guideline and 2022 Considering a caesarean birth publications. Finally, when Dr. Murphy highlights the lack of remuneration for guideline authors, she echoes my own experience of countless hours in unpaid consultation; barring one significant difference. Only authors have the privilege of determining the final version. We also concur on the importance of providing stakeholders the opportunity for public debate. Prior to reading Dr. Murphy’s commentary, I was not aware of the complaint she received, and certainly support individual safeguarding as we all navigate the inevitable disagreements ahead. Nevertheless, open channels of communication and consultation remain a valuable and indispensable method to examine, and in some cases disrupt, established ways of thinking, and they must not be diminished.References1. Murphy DJ. The unwelcome consequences of Guideline authorship. BJOG 2023;00:1-2. 2. McDonagh Hull PM, Thomas K, Skinner E, Dawes A, Christensen P. Re: assisted vaginal birth: green-top guideline no. 26: Montgomery is missing from RCOG’s assisted vaginal birth guideline. BJOG2020;127(10):1297–8. 3. Weston N. Making sense of commissioning Maternity Services in England – some issues for Clinical Commissioning Groups to consider . Royal College of Obstetricians and Gynaecologists, 14 August 2012. 4. Scientists awarded £1million to help women make childbirth choices. University of Aberdeen, 27 September 2022. https://www.abdn.ac.uk/news/16386/. Accessed 5 June 2023.

Cause for optimism in mild hypoxic ischaemic hypoxic encephalopathyWilliam M. Curtin, MD, corresponding authorDivision of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology & Pathology and Laboratory Medicine, Penn State College of Medicine, Penn State Health, Milton S. Hershey Medical Center, Hershey, PA, USAwcurtin@pennstatehealth.psu.eduMail code H103500 University Dr, PO Box 850Hershey, PA 17033-0850Maternal-Fetal Medicine, Rm C3620Phone 717-531-8142/Option #5Fax 717-531-0947Acknowledgements: noneDisclosure of Interests: The author has no conflicts nor competing interests to disclose, financial or otherwise, in connection with this manuscript.Contribution to Authorship: Dr. Curtin alone completed review of the Törn et al. final manuscript entitled “Outcomes in children after mild neonatal hypoxic ischaemic encephalopathy: A population-based cohort study” The writings and opinions expressed in his mini commentary are solely the work of Dr. Curtin.Details of Ethics Approval: not applicable at our institution’s IRB as a commentary is not considered research and does not involve human subjects.Funding: Dr. Curtin neither received nor utilized any funds in writing this mini commentary.The objective of the study by Törn et al. was to determine if mild hypoxic ischaemic encephalopathy (HIE) was associated with severe neurological outcomes utilizing a population-based approach facilitated by five linked Swedish national databases. The rationale given was that while moderate to severe HIE is known to be associated with significant neurological morbidity, long-term disability, and mortality in children, less is known about mild HIE. The authors note that half of the cases of HIE are mild and they cite a systematic review of 250 infants (Conway JM, et al. Early human development . 2018; 120:80-7) showing a 22% prevalence of abnormal neurological outcomes in this disorder. There is therefore potential for significant burden of disease in mild HIE. Törn et al. chose a primary composite outcome that included cerebral palsy, epilepsy, mental retardation and death in children with mild HIE and non HIE cohorts followed up to 6 years of age. With a median follow-up of 3.3 years of age, 17 of 414 (4.1%) and 4786 of 504,661 (0.95%), in the mild HIE and non HIE cohorts respectively, had the composite outcome with an adjusted hazard ratio of 3.85 (95% CI: 2.27-6.50)In 1976 Sarnat and Sarnat reported clinical and EEG features of 21 neonates at term who experienced ischaemic-anoxic encephalopathy (Sarnat HB et al. Arch Neurol. 1976; 33:696–705). This temporal classification divided the infants into three progressively deteriorating stages. Fast forward to the current millennium and Sarnat’s original classification is used to differentiate between infants with mild and moderate/severe HIE, the latter two categories benefiting from therapeutic hypothermia (Jacobs SE et al. Cochrane Database Syst Rev. 2013, Issue 1. Art. No.: CD003311). Seven infants with moderate or severe HIE is the number needed to treat (NNT) to prevent one adverse neurological outcome.Therapeutic hypothermia is not standard of care in mild HIE; however, in a survey of neonatal clinicians from 35 countries the vast majority would support a large randomized controlled trial to examine neurodevelopmental outcomes (Singla M, et al. Neonatology. 2022; 119:712-718). The results from this methodical Swedish cohort study provide data that can be used to direct further research. The composite outcomes in HIE are lower than expected, and one could infer similar outcomes in high resource settings. The data are reassuring and will be useful for clinicians in counseling and reassuring parents with infants affected by mild HIE. Regarding a randomized controlled trial of therapeutic hypothermia in mild HIE: it would appear, based on the data provided by Törn et al., if we hypothesize this therapy would result in a 50% reduction in the composite outcome, the NNT would be approximately 50. This compares unfavorably to the NNT of 7 in moderate/severe HIE. Perhaps, further insight could be gained by review of individual patient data, particularly with respect to antenatal and neonatal course, imaging, EEG, and biochemical data in order to identify a subset that might benefit from therapeutic hypothermia or other novel therapy.Word count: 490

Objectives: To investigate the association and the potential value of prelabour fetal heart rate short-term variability (STV) determined by computerised cardiotocography (cCTG) and maternal-foetal Dopplers in predicting labour outcomes. Design: Prospective cohort study. Setting: The Prince of Wales Hospital, a tertiary maternity unit, in Hong Kong SAR. Population: Women with a term singleton pregnancy in latent phase of labour or prior to labour induction were recruited during May 2019 – November 2021. Methods: Ultrasonographic assessment of foetal growth, Doppler velocimetry and the cCTG monitoring including Dawes-Redman CTG analysis. Main Outcome Measures: Umbilical Cord arterial pH, emergency delivery due to pathological CTG during labour and neonatal intensive care unit (NICU)/special care baby unit (SCBU) admission. Results: Of the 400 cases, 34 (8.5%) women underwent emergency delivery for pathological CTG during labour. A total of 6 (1.50%) and 148 (37.00%) newborns required NICU and SCBU admission, respectively. Middle cerebral artery pulsatility index (MCA-PI) and MCA-PI z-score were significant lower in pregnancies that required emergency delivery for pathological CTG during labour compared with those who did not [1.23 (1.07-1.40) vs 1.40 (1.22-1.64), p=0.002 and 0.55 (±1.07) vs 0.12 (±1.06), p=0.049,]. Umbilical cord arterial pH was associated with STV (r = 0.107, p = 0.035) and the independent predictors for umbilical cord arterial pH were smoking (p = 0.006) and STV (p = 0.025). Conclusions: In pregnant women admitted in latent phase of labour or for induction of labour at term, cCTG STV is associated with umbilical cord arterial pH but not predictive of emergency delivery due to pathological CTG during labour.

A document by Sophie Strong. Click on the document to view its contents.

Recent trends regarding GDM medication use have not been well described in prior literature. We identified pregnant patients enrolled in Tennessee Medicaid with a GDM diagnosis who a delivered in 2007 to 2019. We studied initial GDM medication use by delivery year (overall and by medication type). Over twenty percent of patients filled at least one prescription for GDM medication in the study period, with a significantly increasing prescribing trend over time. Starting in 2016, metformin replaced glyburide as the most common medication prescribed, which corresponds temporally with the emergence of evidence on the safety and effectiveness of different oral hypoglycemic medications and related changes in ACOG practice recommendations. These findings highlight how practice patterns have potential to shift quickly in response to evolving data.

Objective: to explore the impact of attending a clinical placement on selecting a career in obstetrics and gynaecology Design: Mixed methods study Setting: Imperial College London Population: Fifth year medical students attending a clinical placement in obstetrics and gynaecology Methods: Between January 2021- January 2022, questionnaires were used and semi-structured focus groups conducted, which were audio recorded. Descriptive statistics were conducted and a framework analysis on transcribed focus groups. Main outcome measure: the impact of the clinical placement on career choices Results: Six main themes were identified from the analysis; three contributing to considering a career in obstetrics and gynaecology; pregnancy is not an illness, extraordinary experience of observing childbirth and variable specialty and three themes emerged contributing to not considering a career; lack of work-life balance, high stakes specialty and the emotional toll. Even at an undergraduate level, medical students exhibited concerns about the long term feasibility of achieving work life balance and avoiding professional burnout, which was partly attributed to the responsibility of looking after both the woman and baby. Conclusions: Obstetrics and gynaecology is a challenging high stakes specialty but is also highly rewarding. Students experiences of childbirth during a clinical placement appear to contribute to the consideration of a career in obstetrics and gynaecology. It is crucial to provide a supported and realistic introduction to the specialty, to recruit enthusiastic junior doctors who will be resilient to the pressures of obstetrics.

Mini-Commentary on BJOG-22-0480.R1:‘Perinatal outcomes of socially disadvantaged women in Australia: A population-based retrospective cohort study ’